Andreu, David

Bray, Francesca

Cañada, Francisco J.

Díez-Dacal, Beatriz

G. de la Torre, Beatriz

Pérez-Sala, Dolores

Rojas, José M.

Repositorio Institucional de la Universidad de Córdoba

Posters S4. Protein Interactions and Protein Arrays105P. 39THE C-TERMINAL PEPTIDE OF H-RAS AS A TARGET FOR THE COVALENT BINDING OF DRUGS MODULATING RAS-DEPENDENT PATHWAYSFrancesca Bray1, Beatriz Díez-Dacal1, Beatriz G. de la Torre2, José M. Rojas3, Francisco J. Cañada1, David Andreu2 and Dolores Pérez-Sala11Department of Protein Science, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid 2Departamento de Ciencias Experimentales y de la Salud, Univ. Pompeu Fabra, 08003 Barcelona; 3Centro Nacional de Microbiología, ISCIII, 28220 Majadahonda, Spain.Ras proteins are crucial players in differentiation and oncogenesis and thus constitute important drug targets. The localization and activity of Ras proteins are highly dependent on PTMs at their C-termini. In addition to an isoprenylated cysteine, H-Ras, but not other Ras proteins, possesses two cysteine residues (Cys181 and Cys184) in the C-terminal hypervariable domain that act as palmitoylation sites in cells. Therefore, the enzymes responsible for these modifications of H-Ras and the target residues are the subject of intense study as sites for therapeutic intervention. Here we describe the potential of several endogenous and exogenous small molecules to bind to a synthetic peptide from the hypervariable domain of H-Ras proteins. Cyclopentenone prostaglandins (cyPG) are reactive lipidic mediators that may bind covalently to proteins and activate H-Ras dependent pathways. Our results indicate that the dienone cyPG 15-deoxy-Δ12,14-PGJ2 and Δ12-PGJ2 can bind simultaneously Cys181 and Cys184 of H-Ras in vitro, thus possibly inducing important conformational changes of the hypervariable domain. In contrast, single enone cyPG bind the two cysteines independently, whereas cyclopentenone, which lacks the lateral chains of the PG, is a very poor modifier of this peptide and does not activate Ras-dependent pathways in cells. Interestingly, among several small molecules currently being tested, phenylarsine oxide, a widely used tyrosine phosphatase inhibitor, effectively binds H-Ras hypervariable domain. These observations open new perspectives for the study of molecules potentially modulating Ras-dependent pathways.

The C-terminal peptide of H-Ras as a target for the covalent binding of drugs modulating ras-dependent pathways

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Repositorio Institucional de la Universidad de Córdoba